The present invention relates to (2,3)-.alpha.-methylene penam and derivatives thereof. More particularly, the present invention relates to penam derivatives wherein the cyclopropyl group fused to the thiazolidine ring is on the opposite side of the molecule relative to the carboxylic acid, "R.sub.3 NH" and "R.sub.2 " substituent on the beta lactam or penam nuclei.
More specifically, and in an absolute sense, the bridgehead carbon atom located at the 4/5 ring fusion of these new penams has the R absolute configuration (Cahn-Ingold-Prelog method of designating absolute configuration). If the hydrogen atom substituent of this bridgehead carbon atom is designated as extending from the .alpha.-face of the molecule, then the cyclopropylmethylene also extends from the .alpha.-face. The carboxylic acid, "R.sub.3 NH" and "R.sup.2 " substituents are all on the .beta.-face of the molecule. It should be noted that in this special arrangement, the absolute configuration of the carbon atom bearing the carboxylic acid substituent is opposite to all known penam antibacterials.
2,3-Lower alkyl alkylene penam-3-carboxylic acid derivatives wherein the fused cyclopropyl group is set forth without any stereochemical configuration are broadly disclosed in U.S. Pat. No. 3,904,607 to Kamiya et al. issued Sept. 9, 1975. An analysis of the disclosure indicates that the compounds produced have the fused cyclopropyl group on the .beta.-face of the molecule (with the bridgehead carbon atom located on the 4/5 ring fusion having the R absolute configuration as noted above). Such compounds do not have the level and spectrum of antimicrobial activity of the present compounds.
Similar compounds have also been disclosed in U.S. Pat. No. 4,393,003 to Keith et al. issued July 12, 1983 but as noted above these compounds have the cyclopropyl fused ring in the .beta.-position as stereochemically depicted in the Patent. Again the spectrum and activity levels are inferior to the present compounds.
A further article by Keith et al. in Tetrahedron Letters, 39(15), pages 2445-2458, 1983 discusses the mechanisms of action due to conformational differences in penam nuclei and their effect on penicillin antibacterial activity. Such disclosure does not include compounds wherein the methylene of the cyclopropyl group is in a "down" or .alpha.-configuration and the carboxylic acid is in an opposite "unnatural" absolute configuration.